The family of bacterial superantigens including the two dozens of pyrogenic exotoxins secreted by Staphylococcus aureus (SEB) and Streptococcus pyogenes (SPEA) and toxic shock syndrome toxin-1 (TSST-1) are most potent and could potentially be used for bioterrorism. The SEB is classified as priority 'B' in the national biodefense strategy. The current scenarios of biological warfare and bioterrorism are more likely to entail the use of the superantigen mixtures, readily available by culturing the bacteria. Therefore, there is an unmet need to develop broad-spectrum countermeasures. We have successfully demonstrated that the antagonist peptide 6343, designed based on the two highly conserved regions of superantigens from Staphylococcus and Streptococcus, blocked actions of a wide range of superantigens, including SEB, SPEC and TSST-I. We have also demonstrated by immunoblotting that the anti-6348 antibody, which specifically recognizes the peptide 6343, also recognized a number of superantigen toxins. Further experiments have shown that the peptide and the antibody blocked the actions of toxins in PBMC proliferation assay and in mice and rabbits. Taken together, our data suggest that the anti-toxin activities of the peptide and antibody were broad-spectrum in nature. Using a similar scientific rationale, Arad et al. 2001 designed an antagonist peptide that also inhibited actions of a variety of superantigen toxins in cell based assays and in animal models. Our more recent results indicate that shorter peptides, derived from the sequence of 6343, with unnatural amino acid residues were equally effective in blocking actions of all superantigen toxins tested. Hence, proteolytic destruction of these peptides would be unlikely when administered orally. The overall goal of this grant proposal is to identify a lead peptide and its antibody and evaluate their efficacies in animal models. Successful accomplishment of these goals will permit us to take the lead candidates into clinical trials in humans. [unreadable] [unreadable]